Although hepatitis C virus (HCV) is a leading cause of morbidity and mortality worldwide, the effects of viral gene expression on infected cells remain unclear in vivo. Previously, we reported the construction of transgenic mice expressing HCV structural proteins (core, E1 and E2) and showed that expression of HCV structural proteins is not directly cytopathic in this animal model. Using DNA immunization, we were able to induce antibody and T cell proliferative responses against HCV structural proteins in these transgenic animals. Studies are in progress to determine whether cytotoxic T cell response or hepatitis could be elicited using this approach. Our laboratory is also generating transgenic mice expressing HCV polyprotein full-length and are developing a system for inducible expression of HCV transgene using the tetracycline-inducible system. Using either the LacZ or SV40 Tag as a reporter transgene, our preliminary studies suggested that a tightly regulated transgene expression could be achieved in the liver. These animal will provide a useful animal model not only to address issues of immunopathogenesis and cytopathic potential of HCV gene products but also to study HCV replication in vivo.